As Component Project 1 was being drafted, we made the startling observations that the SmD variants of M. avium, the drug-sensitive form, are largely devoid of the copious polyglycosylated GPLs which dominate the SmT, drug-resistant variants and that the rough GPL-variant converts to the pathogenic SmT variant in the mouse. These observations indicate that M. avium GPL undergo phase variation--the spontaneous loss and acquisition strategies and places much emphasis on a basic molecular approach. Over a wide range of serovars from AIDS patients, we propose to demonstrate that the SmD variants are largely devoid of the specific polar GPL and by structural analysis and appropriate enzymology identify the defective enzyme. This target enzyme in the SmT variant, perhaps a glycosyltransferase, will be the focus of a "designer drug" strategy emulating the innovative approach to inhibition of LPS synthesis. The other major entities of the cell wall of M. avium--lipoarabinomannan, the arabinogalactan-peptidoglycan complex, the proteins of cell walls and membranes--will be chemically characterized towards ultimate definition of the permeability barrier.